Non-peptide oxytocin receptor agonists

Abstract

Disclosed herein are compounds according to Formula I; a pharmaceutical composition including, consisting essentially of, or consisting of: a pharmaceutically acceptable compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient; the use of compounds of Formula I in the preparation of a medicament; and a method including administering a pharmaceutical compositions comprising the compound of Formula I to a patient. The compounds, compositions, use, and methods are directed to the treatment of neurological, psychiatric disorders which are characterised by a fundamental disruption of social behaviour, and substance use disorders.

What is claimed is: 
     
       1. A pharmaceutical composition comprising: a pharmaceutically acceptable compound of Formula I and a pharmaceutically acceptable carrier, diluent, or excipient: 
       
         
           
           
               
               
           
         
         wherein R1, R3, R4, R5, and R6 are each independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, substituted or unsubstituted —NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein R2 is selected from the group consisting of: H, F, Br, I, NH 2 , NO 2 , OH, ON═O, substituted methyl, substituted or unsubstituted C 2 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, substituted or unsubstituted —NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein each R1, R2, R3, R4, R5, or R6 that is a substituted aryl or a substituted heterocyclyl includes one or more substituent(s) selected from the group consisting of F, Cl, Br, I, NH 2 , N═O, NO 2 , NHCH 3 , OH, OCH 3 , OC≡N, ON═O, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , SC≡N, COOH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) ; 
         wherein X is a cyclic structure selected from the group consisting of: a fused or unfused aryl; a fused or unfused heterocyclyl; and a fused or unfused cycloalkyl; and 
         wherein X1 represents one to three atoms or moieties independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, substituted or unsubstituted —NHC 2 -C 4  alkynyl, —COOH, —C 1  alkyl-COOH, —COOC 1 -C 2  alkyl, —COOC 1 -C 2  alkaryl, —C 1  alkyl-COOC 1 -C 2  alkyl, —C 1 -C 2  alkaryl, —OC 1 -C 2  alkaryl, —NC 1 -C 2  alkaryl, —C 1 -C 2  alkyl-heterocyclyl, —OC 1 -C 2  alkyl-heterocyclyl, and —NC 1 -C 2  alkyl-heterocyclyl; 
         wherein each alkyl, alkenyl, alkynyl, alkaryl, or alkyl-heterocyclyl that is independently substituted with one or more substituent selected from the group consisting of: F, Cl, Br, I, ≡N, ═NH, NH 2 , N═O, NO 2 , NHCH 3 , N═C═O, N═C═S, ═O, OH, OCH 3 , OC≡N, ON═O, ═S, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , and SC≡N; 
         wherein each m is an integer selected from 0, 1, and 2; and 
         each n is an integer selected from 0, 1, and 2. 
       
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the cyclic structure is selected from the group consisting of: fused or unfused aryl groups; fused or unfused 5, 6-, or 7-membered heterocyclic groups having one or more hetero ring atoms selected from N, O, and S; and a 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15-, or 16-membered mono-, bridged bi-, or bridged tri-cycloalkyl groups. 
     
     
       3. The pharmaceutical composition of  claim 1 , wherein: the aryl group is an unfused aryl group, the heterocyclic group is an unfused heterocyclic group having only a single hetero ring atom, and the cycloalkyl is a bridged bi- or tri-cyclic alkyl group. 
     
     
       4. The pharmaceutical composition of  claim 1 , wherein the cyclic structure is selected from the group consisting of: phenyl, pyridyl, and adamantyl. 
     
     
       5. The pharmaceutical composition of  claim 1 , wherein R1, R3, R4, R5, and R6 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) . 
     
     
       6. The pharmaceutical composition of  claim 1 , wherein R2 is independently selected from the group consisting of: H, F, Br, I, OH, CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) . 
     
     
       7. The pharmaceutical composition of  claim 1 , wherein the fused or unfused aryl at X is a phenyl of the form: 
       
         
           
           
               
               
           
         
         wherein each A1, A2, A3, A4, or A5 is independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, and substituted or unsubstituted —NHC 2 -C 4  alkynyl; and 
         wherein optionally one or more of A1 and A2, and/or A2 and A3, and/or A3 and A4, and/or A4 and A5 together form a fused ring structure. 
       
     
     
       8. The pharmaceutical composition of  claim 7 , wherein A1, A2, A3, A4, or A5 are each independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 2  alkyl, substituted or unsubstituted C 2  alkenyl, substituted or unsubstituted C 2  alkynyl, substituted or unsubstituted —OC 1 -C 2  alkyl, substituted or unsubstituted —OC 2  alkenyl, substituted or unsubstituted —OC 2  alkynyl, substituted or unsubstituted —NHC 1 -C 2  alkyl, substituted or unsubstituted —NHC 2  alkenyl, and substituted or unsubstituted —NHC 2  alkynyl. 
     
     
       9. The pharmaceutical composition of  claim 8 , wherein A1, A2, A3, A4, or A5 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) . 
     
     
       10. The pharmaceutical composition of  claim 1 , wherein the fused or unfused heterocyclyl at X is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         Z is the hetero ring atom, and is selected from the group consisting of N, S, and O; and 
         each H1, H2, H3, H4, or H5 that is present is independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, substituted or unsubstituted —NHC 2 -C 4  alkynyl; and 
         wherein optionally one or more of H1 and H2, and/or H2 and H3, and/or H3 and H4, and/or H4 and H5 together form a fused ring structure. 
       
     
     
       11. The pharmaceutical composition of  claim 10 , wherein Z is N. 
     
     
       12. The pharmaceutical composition of  claim 10 , wherein each H1, H2, H3, H4, or H5 that is present is independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 2  alkyl, substituted or unsubstituted C 2  alkenyl, substituted or unsubstituted C 2  alkynyl, substituted or unsubstituted —OC 1 -C 2  alkyl, substituted or unsubstituted —OC 2  alkenyl, substituted or unsubstituted —OC 2  alkynyl, substituted or unsubstituted —NHC 1 -C 2  alkyl, substituted or unsubstituted —NHC 2  alkenyl, and substituted or unsubstituted —NHC 2  alkynyl. 
     
     
       13. The pharmaceutical composition of  claim 12 , wherein each H1, H2, H3, H4, or H5 that is present is independently selected from the group consisting of: H, F, Cl, Br, I, OH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) . 
     
     
       14. The pharmaceutical composition of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       15. A compound of Formula I, 
       
         
           
           
               
               
           
         
         wherein R1, R3, R4, R5, an R6 are each independently selected from the group consisting of: H, F, Cl, Br, I, NH 2 , NO 2 , OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, substituted or unsubstituted —NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein R2 is selected from the group consisting of: H, F, Br, I, NH 2 , NO 2 , OH, ON═O, substituted methyl, substituted or unsubstituted C 2 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, substituted or unsubstituted —NHC 2 -C 4  alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heterocyclyl; 
         wherein each R1, R2, R3, R4, R5, or R6 that is a substituted aryl or a substituted heterocyclyl includes one or more substituents selected from the group consisting of F, Cl, Br, I, NH 2 , N═O, NO 2 , NHCH 3 , OH, OCH 3 , OC≡N, ON═O, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , SC≡N, COOH, CH 3 , CH m F (3-m) , CH m Cl (3-m) , CH m Br (3-m) , OCH 3 , OCH m F (3-m) , OCH m Cl (3-m) , and OCH m Br (3-m) ; 
         wherein X is a cyclic structure selected from the group consisting of: a fused or unfused aryl; a fused or unfused heterocyclyl; and a fused or unfused cycloalkyl; and 
         wherein X1 represents one to three atoms or moieties independently selected from the group consisting of: H, F, Cl, Br, I, OH, ON═O, substituted or unsubstituted C 1 -C 4  alkyl, substituted or unsubstituted C 2 -C 4  alkenyl, substituted or unsubstituted C 2 -C 4  alkynyl, substituted or unsubstituted —OC 1 -C 4  alkyl, substituted or unsubstituted —OC 2 -C 4  alkenyl, substituted or unsubstituted —OC 2 -C 4  alkynyl, substituted or unsubstituted —NHC 1 -C 4  alkyl, substituted or unsubstituted —NHC 2 -C 4  alkenyl, substituted or unsubstituted —NHC 2 -C 4  alkynyl, —COOH, —C 1  alkyl-COOH, —COOC 1 -C 2  alkyl, —COOC 1 -C 2  alkaryl, —C 1  alkyl-COOC 1 -C 2  alkyl, —C 1 -C 2  alkaryl, —OC 1 -C 2  alkaryl, —NC 1 -C 2  alkaryl, —C 1 -C 2  alkyl-heterocyclyl, —OC 1 -C 2  alkyl-heterocyclyl, and —NC 1 -C 2  alkyl-heterocyclyl; 
         wherein each alkyl, alkenyl, or alkynyl that is independently substituted with one or more substituent selected from the group consisting of: F, Cl, Br, I, ═NH, N═O, NO 2 , NHCH 3 , N═C═O, N═C═S, ═O, OH, OCH 3 , OC≡N, ON═O, ═S, SH, SCH 3 , S(═O) n OH, S(═O) n CH 3 , and SC≡N; 
         wherein each m is an integer selected from 0, 1, and 2; and 
         each n is an integer selected from 0, 1, and 2; and 
         wherein the compound is not selected from the group consisting of: 
         i) 
       
       
         
           
           
               
               
           
         
       
       when A1 is H; A2 is CH 3 ; and A3 is any one of CH 2 CH 2 COOH, CH═CHCOOH, OCH 2 CH 2 CH 2 COOH, CH 2 CH 2 C(═O)NHCH 3 , NH 2 , or NO 2 ; or 
       
         
           
           
               
               
           
         
       
       when A1 is H; A2 is H; and A3 is OH; or
 iii) a compound wherein the substituted or unsubstituted cycloalkyl is a substituted cyclohexane group. 
 
     
     
       16. A compound selected from the group consisting of: